Summary - Abstract Recent work in our laboratories has shown, in both noise-induced and age-related hearing loss, that the most vulnerable elements in the inner ear are synaptic connections between hair cells and cochlear neurons, and that this synaptopathy can be widespread (> 50%) even in cochlear regions with no hair cell loss. Although this primary neural degeneration has little effect on auditory/cochlear thresholds (thus, a ?hidden hearing loss?), partial de-afferentation of surviving inner hair cells is likely a major cause of difficulties understanding speech in a noisy environment and may be a key elicitor of tinnitus. Synaptic loss silences the affected neurons, absent a cochlear implant, however the slow death of the cell bodies and central projections offers a long therapeutic window. Indeed, we have recently shown that neurotrophin-based therapies can elicit synaptogenesis and partial functional recovery even in the adult ear. Here, we extend our prior work on cochlear synaptopathy in both basic-science and translational directions via four closely coupled Aims in our mouse model of noise-induced synaptopathy. Aim 1 is a neurophysiological and intracellular labeling study of single auditory nerve fibers (ANFs) testing the hypothesis that, by eliminating ANFs with high thresholds and low spontaneous rates (SRs), synaptopathy compromises stimulus coding in the presence of background noise. We also use the single-unit data to optimize a diagnostic test for hidden hearing loss based on the dynamic range of masking as revealed by auditory evoked potentials. Building on preliminary results showing 100% transfection efficiency of inner hair cells following cochlear injection of a designer adeno-associated virus, Aim 2 uses virally mediated neurotrophin overexpression to extend the trauma-treatment interval over which synaptopathy can be rescued in the adult ear, beyond the success we have already shown at 24 hrs post exposure. In Aim 3, we return to neurophysiology and intracellular labeling to ask whether regenerated ANFs from Aim 2 recapitulate normal ANF response properties, especially with respect to the robustness of stimulus coding in noise. Lastly, Aim 4 uses a novel behavioral assay for tinnitus to ask whether synaptopathy per se is necessary for the generation of tinnitus, and whether the synaptopathy repair achieved in Aim 2 can also reduce or eliminate the tinnitus percept in animals.